Optically active quaternary ammonium salt having axial asymmetry, and method for producing alpha-amino acid and derivative thereof by using the same

ABSTRACT

The present invention discloses an optically active quarternary ammonium salt having axial asymmetry and a method for producing an α-amino acid and a derivative thereof using the same. The optically active quarternary ammonium salt having axial asymmetry of the present invention is a chiral phase-transfer catalyst that has a simple structure and that can be produced in a smaller number of process steps. The compound of the present invention is very useful as a phase-transfer catalyst in the synthesis of an α-alkyl-α-amino acid and a derivative thereof as well as an α,α-dialkyl-α-amino acid and a derivative thereof. Therefore, the compound of the present invention can be used in the development of novel foods and pharmaceuticals.

TECHNICAL FIELD

The present invention relates to an optically active quaternary ammoniumsalt having axial asymmetry and a method for producing the same. Thepresent invention further relates to a method for producing an opticallyactive α-amino acid and derivatives thereof by using this opticallyactive quaternary ammonium salt having axial asymmetry as aphase-transfer catalyst.

BACKGROUND ART

α-Alkyl-α-amino acids represented by the formula H₂NCH(R)COOH are veryimportant naturally-occurring α-amino acids. α-Alkyl-α-amino acids inwhich the α-carbon has an L-configuration are a structural component ofproteins (polypeptide chains) that exist in animals, plants, andmicroorganisms, for example. The D-form of α-alkyl-α-amino acids existsin plants, fungi and microorganisms as a structural component ofnon-proteogenic compounds. On the other hand, α,α-dialkyl-α-amino acidsare recently gaining attention because of their unique functions,including the fact that they are stereochemically stable and that whenthey are incorporated into peptides, those peptides are not susceptibleto enzymatic hydrolysis by proteases (see Bellier, B. et al. (1997). J.Med. Chem. 40:3947 and Mossel, E. et al. (1997). Tetrahedron Asymmetry8:1305). These properties have led α,α-dialkyl-α-amino acids to beconsidered for use as chiral building blocks for the synthesis ofpeptides having enhanced activity, effective enzyme inhibitors, andcompounds having other various biological activities. Methods forsynthesizing non-proteogenic α-amino acids, particularlyα,α-dialkyl-α-amino acids, by selectively building the stereochemistryof the α-carbon have been investigated, but at the present time, apractical method has not yet been found.

Chiral phase-transfer catalysts that allow stereoselective alkylation ofglycine derivatives are easy to use and can be applied widely, and thushave become increasingly important in the field of process chemistry. Alarge amount of research into designing phase-transfer catalysts hasbeen conducted mainly by using cinchona alkaloid derivatives, and todate several useful methods have been reported (e.g., see Shioiri, T. etal., Stimulating Concepts in Chemistry, edited by Vogtle, F. et al.,WILEY-VCH: Weinheim, p. 123, 2000; and O'Donnell, M. J. (2001).Aldrichimica Acta, 34:3). However, when such phase-transfer catalystsare used in a reaction, various problems are caused, including the factthat halogen-based solvents are employed, the reaction is sluggish, andlow temperature conditions are required. In particular, the use ofchiral phase-transfer catalysts derived from such cinchona alkaloids isnot particularly efficient in the synthesis of α,α-dialkyl-α-aminoacids.

The present inventors have prepared an optically active quaternaryammonium salt having axial asymmetry, and have clearly shown that it canbe used as a phase-transfer catalyst for stereoselectively synthesizingα-alkyl-α-amino acids and α,α-dialkyl-α-amino acids (see JapaneseLaid-Open Patent Publication Nos. 2001-48866 and 2003-81976; and Ooi, T.et al. (2000). J. Am. Chem. Soc. 122:5228). For example, aspiro-compound represented by the following formula is very effectivefor stereoselectively producing α,α-dialkyl-α-amino acids because itcatalyzes the stereoselective double alkylation of glycine derivativesand the stereoselective monoalkylation of α-alkyl-α-amino acidderivatives:

(where PhF₃ represents a 3,4,5-trifluorophenyl group). However, thepreparation of such spiro-type catalysts requires many process steps;for example, if chiral binaphthol, which is easily available, is used asthe starting material, then eleven process steps are required just toprepare the portion represented by the left half of the chemicalstructure formula of the catalyst. Therefore, it has been pointed outthat preparation of conventional optically active quaternary ammoniumsalts having axial asymmetry may be extremely time-consuming and costly.

DISCLOSURE OF INVENTION

It is an object of the present invention to provide a chiralphase-transfer catalyst that has a simple structure and that can beproduced in a smaller number of process steps.

The present invention provides a compound represented by Formula (I)below:

wherein

R² and R^(2′) are each independently:

-   -   a hydrogen atom; or    -   an aryl group, wherein the aryl group may be substituted with at        least one group selected from the group consisting of:        -   a C₁ to C₄ alkyl group that may be branched and that may be            substituted with a halogen atom,        -   a C₁ to C₅ alkoxy group that may be branched and that may be            substituted with a halogen atom,        -   an aryl group that may be substituted with a halogen atom or            a C₁ to C₄ alkyl group that may be branched and that may be            substituted with a halogen atom, and        -   a halogen atom;

R³ and R^(3′) are each independently:

-   -   a C₁ to C₅ alkoxy group that may be substituted with a halogen        atom and/or an aryl group, and/or that may be branched or form a        cyclic group;

R⁴ and R^(4′) are each independently a group selected from the groupconsisting of:

-   -   (i) a hydrogen atom;    -   (ii) a halogen atom;    -   (iii) a C₁ to C₆ alkyl group that may be branched or form a        cyclic group and that may be substituted with a halogen atom;    -   (iv) a C₂ to C₆ alkenyl group that may be branched or form a        cyclic group and that may be substituted with a halogen atom;    -   (v) a C₂ to C₆ alkynyl group that may be branched or form a        cyclic group and that may be substituted with a halogen atom;    -   (vi) an aralkyl group, wherein the aryl moiety constituting the        aralkyl group may be substituted with at least one group        selected from the group consisting of:        -   a C₁ to C₄ alkyl group that may be branched and that may be            substituted with a halogen atom,        -   a C₁ to C₅ alkoxy group that may be branched and that may be            substituted with a halogen atom,        -   an aryl group that may be substituted with a halogen atom or            a C₁ to C₄ alkyl group that may be branched and that may be            substituted with a halogen atom, and        -   a halogen atom; and    -   (vii) an aryl group, wherein the aryl group may be substituted        with at least one group selected from the group consisting of:        -   a C₁ to C₄ alkyl group that may be branched and that may be            substituted with a halogen atom,        -   a C₁ to C₅ alkoxy group that may be branched and that may be            substituted with a halogen atom,        -   an aryl group that may be substituted with a halogen atom or            a C₁ to C₄ alkyl group that may be branched and that may be            substituted with a halogen atom, and        -   a halogen atom;

R⁷ and R⁸ are each independently a group selected from the groupconsisting of:

-   -   (i) a C₁ to C₃₀ alkyl group that may be branched or form a        cyclic group and that may be substituted with a halogen atom;    -   (ii) a C₂ to C₁₂ alkenyl group that may be branched or form a        cyclic group and that may be substituted with a halogen atom;    -   (iii) a C₂ to C₁₂ alkynyl group that may be branched or form a        cyclic group and that may be substituted with a halogen atom;        and    -   (iv) an aryl group, wherein the aryl group may be substituted        with at least one group selected from the group consisting of:        -   a C₁ to C₄ alkyl group that may be branched and that may be            substituted with a halogen atom,        -   a C₁ to C₅ alkoxy group that may be branched and that may be            substituted with a halogen atom,        -   an aryl group that may be substituted with a halogen atom or            a C₁ to C₄ alkyl group that may be branched and that may be            substituted with a halogen atom, and        -   a halogen atom; or    -   R⁷ and R⁸ are taken together to form a divalent group selected        from the group consisting of:    -   —(CH₂)_(m)— (where m is an integer from 2 to 8);

(where R²⁷, R²⁸, R²⁹, R³², R³³ and R³⁴ are each independently a groupselected from the group consisting of:

-   -   a hydrogen atom;    -   a C₁ to C₈ alkyl group that may be branched or form a cyclic        group, and/or that may be substituted with a halogen atom;    -   a C₂ to C₈ alkenyl group that may be branched or form a cyclic        group, and/or that may be substituted with a halogen atom;    -   a C₂ to C₈ alkynyl group that may be branched or form a cyclic        group, and/or that may be substituted with a halogen atom;    -   an aryl group, which may be substituted with a C₁ to C₄ alkyl        group that may be substituted with a halogen atom, a C₁ to C₃        alkoxy group that may be substituted with a halogen atom, an        aryl group that may be substituted with a C₁ to C₄ alkyl group        that may be substituted with a halogen atom, a cyano group, a        halogen atom, a nitro group, —NR³⁰R³¹ (where R³⁰ and R³¹ are        each independently a hydrogen atom or a C₁ to C₄ alkyl group        that may be branched and that may be substituted with a halogen        atom), or a cyclic amino group that is formed by a C₂ to C₈        alkylene group; and    -   an aralkyl group, which has an aryl moiety that may be        substituted with a C₁ to C₄ alkyl group that may be substituted        with a halogen atom, a C₁ to C₃ alkoxy group that may be        substituted with a halogen atom, a cyano group, a halogen atom,        a nitro group, —NR³⁰R³¹ (where R³⁰ and R³¹ are each        independently a hydrogen atom or a C₁ to C₄ alkyl group that may        be branched and that may be substituted with a halogen atom), or        a cyclic amino group that is formed by a C₂ to C₈ alkylene        group), and

X⁻ is an anion selected from the group consisting of a halide anion,SCN⁻, HSO₄ ⁻, HF₂—, CF₃SO₃—, CH₃—C₆H₄—SO₃—, and CH₃SO₃—.

In one embodiment, R² and R^(2′) of the compound represented by Formula(I) are both hydrogen atoms.

In one embodiment, R² and R^(2′) of the compound represented by Formula(I) are both aryl groups, wherein the aryl group may be substituted withat least one group selected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

In one embodiment, R⁴ and R^(4′) of the compound represented by Formula(I) are both aryl groups, wherein the aryl group may be substituted withat least one group selected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

-   -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

The present invention also provides a method for producing the compoundrepresented by Formula (I) described above, the method comprising:

a step of reacting a compound represented by Formula (II) below:

with a secondary amine represented by Formula (III) below:

in an organic solvent in the presence of an acid-scavenging agent,

wherein in Formula (II),

R² and R^(2′) are each independently:

a hydrogen atom; or

an aryl group, wherein the aryl group may be substituted with at leastone group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom;        R³ and R^(3′) are each independently:

a C₁ to C₅ alkoxy group that may be substituted with a halogen atomand/or an aryl group, and/or that may be branched or form a cyclicgroup;

R⁴ and R^(4′) are each independently a group selected from the groupconsisting of:

(i) a hydrogen atom;

(ii) a halogen atom;

(iii) a C₁ to C₆ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(iv) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(v) a C₂ to C₆ alkynyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(vi) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and

(vii) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom, and        Z is a halogen atom, and

in Formula (III),

R⁷ and R⁸ are each independently a group selected from the groupconsisting of:

(i) a C₁ to C₃₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(ii) a C₂ to C₁₂ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iii) a C₂ to C₁₂ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom; and

(iv) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of;

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; or        R⁷ and R⁸ are taken together to form a divalent group selected        from the group consisting of:

—(CH₂)_(m)— (where in is an integer from 2 to 8);

(where R²⁷, R²⁸, R²⁹, R³², R³³ and R³⁴ are each in dependently a groupselected from the group consisting of:

a hydrogen atom;

a C₁ to C₈ alkyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

a C₂ to C₈ alkenyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

a C₂ to C₈ alkynyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

an aryl group, which may be substituted with a C₁ to C₄ alkyl group thatmay be substituted with a halogen atom, a C₁ to C₃ alkoxy group that maybe substituted with a halogen atom, an aryl group that may besubstituted with a C₁ to C₄ alkyl group that may be substituted with ahalogen atom, a cyano group, a halogen atom, a nitro group, —NR³⁰R³¹(where R³⁰ and R³¹ are each independently a hydrogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom), or a cyclic amino group that is formed by a C₂ to C₈alkylene group; and

an aralkyl group, which has an aryl moiety that may be substituted witha C₁ to C₄ alkyl group that may be substituted with a halogen atom, a C₁to C₃ alkoxy group that may be substituted with a halogen atom, a cyanogroup, a halogen atom, a nitro group, —NR³⁰R³¹ (where R³⁰ and R³¹ areeach independently a hydrogen atom or a C₁ to C₄ alkyl group that may bebranched and that may be substituted with a halogen atom), or a cyclicamino group that is formed by a C₂ to C₈ alkylene group).

In one embodiment, R² and R^(2′) of the compound represented by Formula(II) are both hydrogen atoms.

In one embodiment, R² and R^(2′) of the compound represented by Formula(II) are both aryl groups, wherein the aryl group may be substitutedwith at least one group selected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

In one embodiment, R⁴ and R^(4′) of the compound represented by Formula(II) are both aryl groups, wherein the aryl group may be substitutedwith at least one group selected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

The present invention further provides a compound represented by Formula(II) below:

whereinR² and R^(2′) are each independently:

a hydrogen atom; or

an aryl group, wherein the aryl group may be substituted with at leastone group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom;        R³ and R^(3′) are each independently:

a C₁ to C₅ alkoxy group that may be substituted with a halogen atomand/or an aryl group, and/or that may be branched or form a cyclicgroup;

R⁴ and R^(4′) are each independently a group selected from the groupconsisting of:

(i) a hydrogen atom;

(ii) a halogen atom;

(iii) a C₁ to C₆ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(iv) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(v) a C₂ to C₆ alkynyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(vi) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and

(vii) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and        Z is a halogen atom.

The present invention also provides a compound represented by Formula(VII) below:

whereinR³ and R^(3′) are each independently:

a C₁ to C₅ alkoxy group that may be substituted with a halogen atomand/or an aryl group, and/or that may be branched or form a cyclicgroup;

Z¹ is a halogen atom; andZ² is a hydrogen atom or a halogen atom.

The present invention further provides a method for stereoselectivelyproducing a compound represented by Formula (VI):

the method comprising:

a step of alkylating a compound represented by Formula (IV):

with a compound of Formula (V):

R¹⁸—W   (V)

using a compound represented by Formula (I) that is pure with respect toits axial asymmetry as a phase-transfer catalyst:

in a medium in the presence of an inorganic base,

wherein in Formula (I),

R² and R^(2′) are each independently:

a hydrogen atom; or

an aryl group, wherein the aryl group may be substituted with at leastone group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom;        R³ and R^(3′) are each independently:

a C₁ to C₅ alkoxy group that may be substituted with a halogen atomand/or an aryl group, and/or that may be branched or form a cyclicgroup;

R⁴ and R^(4′) are each independently a group selected from the groupconsisting of:

(i) a hydrogen atom;

(ii) a halogen atom;

(iii) a C₁ to C₆ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(iv) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(v) a C₂ to C₆ alkynyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(vi) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and

(vii) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom;        R⁷ and R⁸ are each independently a monovalent organic group, or        R⁷ and R⁸ are taken together to form a divalent organic group,        and        X⁻ is a halide anion;

in Formulae (IV) and (VI),

R¹⁴ and R¹⁵ are each independently:

(i) a hydrogen atom; or

(ii) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom,

with the proviso that a case where R¹⁴ and R¹⁵ are both hydrogen atomsis excluded;

R¹⁶ is a group selected from the group consisting of:

(i) a hydrogen atom;

(ii) a C₁ to C₁₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom, wherein the alkyl groupmay be substituted with a C₁ to C₅ alkoxy group that may be branched andthat may be substituted with a halogen atom;

(iii) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iv) a C₂ to C₆ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(v) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and (vi) an aryl group, wherein the aryl group        may be substituted)

with at least one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and

R¹⁷ is a C₁ to C₈ alkyl group that may be branched or form a cyclicgroup, in Formulae (V) and (VI),

R¹⁸ is a group selected from the group consisting of:

(i) a C₁ to C₁₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom, wherein the alkyl groupmay be substituted with a C₁ to C₅ alkoxy group that may be branched andthat may be substituted with a halogen atom;

(ii) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iii) a C₂ to C₆ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iv) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and

(v) a C₃ to C₉ propargyl group or substituted propargyl group that maybe branched and that may be substituted with a halogen atom, in Formula(V),

W is a functional group having a leaving ability, and in Formula (VI),* indicates a newly produced asymmetric center.

In one embodiment, R⁷ and R⁸ of the compound represented by Formula (I)are each independently a group selected from the group consisting of:

(i) a C₁ to C₃₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(ii) a C₂ to C₁₂ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iii) a C₂ to C₁₂ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom; and

(iv) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom; or

R⁷ and R⁸ are taken together to form a divalent group selected from thegroup consisting of:

—(CH₂)_(m)— (where in is an integer from 2 to 8);

(where R²⁷, R²⁸, R²⁹, R³², R³³ and R³⁴ are each i n dependently a groupselected from the group consisting of:

a hydrogen atom;

a C₁ to C₃ alkyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

a C₂ to C₈ alkenyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

a C₂ to C₈ alkynyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

an aryl group, which may be substituted with a C₁ to C₄ alkyl group thatmay be substituted with a halogen atom, a C₁ to C₃ alkoxy group that maybe substituted with a halogen atom, an aryl group that may besubstituted with a C₁ to C₄ alkyl group that may be substituted with ahalogen atom, a cyano group, a halogen atom, a nitro group, —NR³⁰R³¹(where R³⁰ and R³¹ are each independently a hydrogen atom, or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom), or a cyclic amino group that is formed by a C₂ to C₈alkylene group; and

an aralkyl group, which has an aryl moiety that may be substituted witha C₁ to C₄ alkyl group that may be substituted with a halogen atom, a C₁to C₃ alkoxy group that may be substituted with a halogen atom, a cyanogroup, a halogen atom, a nitro group, —NR³⁰R³¹ (where R³⁰ and R³¹ areeach independently a hydrogen atom or a C₁ to C₄ alkyl group that may bebranched and that may be substituted with a halogen atom), or a cyclicamino group that is formed by a C₂ to C₈ alkylene group).

In a further embodiment, R² and R^(2′) of the compound represented byFormula (I) are both hydrogen atoms.

In a further embodiment, R² and R^(2′) of the compound represented byFormula (I) are both aryl groups, wherein the aryl group may besubstituted with at least one group selected from the group consistingof:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

In a further embodiment, R⁴ and R^(4′) of the compound represented byFormula (I) are both aryl groups, wherein the aryl group may besubstituted with at least one group selected from the group consistingof:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

In one embodiment, the inorganic base is used in the form of an aqueousinorganic-base solution.

In a further embodiment, the inorganic base in the aqueousinorganic-base solution is used in a ratio of at least 0.5 equivalentsup to 280 equivalents with respect to 1 equivalent of the compoundrepresented by Formula (IV).

In a still further embodiment, a concentration of the aqueousinorganic-base solution is 10 w/w % to 70 w/w %.

In a still further embodiment, the compound represented by Formula (I)is used in a ratio of 0.0001 mol % to 5 mol % with respect to 1 mol ofthe compound represented by Formula (IV).

In a still further embodiment, a volume ratio between the medium and theaqueous inorganic-base solution is 7:1 to 1:5.

The present invention also provides a method for producing an opticallyactive α-amino acid, the method comprising:

a step of hydrolyzing an imino group (R¹⁴R¹⁵C═N—) of a compoundrepresented by Formula (VI) that is obtained using any one of theabove-described method under acidic conditions:

(where R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are the same groups as defined above);and

a step of hydrolyzing an ester group (—CO₂R¹⁷) of the acidic-hydrolysisproduct under acidic or basic conditions.

The present invention also provides a method for producing an opticallyactive α-amino acid, the method comprising:

a step of hydrolyzing an ester group (—CO₂R¹⁷) of a compound representedby Formula (VI) that is obtained using any one of the above-describedmethod under basic conditions:

(where R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are the same groups as defined above);and

a step of hydrolyzing an imino group (R¹⁴R¹⁵C═N—) of thebasic-hydrolysis product under acidic conditions.

The present invention provides a chiral phase-transfer catalyst that hasa more simplified structure. This phase-transfer catalyst can beproduced in a smaller number of process steps than conventional ones.Thus, the phase-transfer catalyst of the present invention, which can beprovided more easily, can be used, for example, in the synthesis ofα-alkyl-α-amino acid derivatives and α,α-dialkyl-α-amino acids.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the terms used in the present invention will be defined.

The phrase “C₁ to C_(n) alkyl group that may be branched or form acyclic group” (where n is an integer) includes any linear alkyl grouphaving 1 to n carbon atoms, any branched alkyl group having 3 to ncarbon atoms, and any cyclic alkyl group having 3 to n carbon atoms.Examples of linear alkyl groups having 1 to 6 carbon atoms includemethyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Examples ofbranched alkyl groups having 3 to 6 carbon atoms include isopropyl,isobutyl, tert-butyl, and isopentyl. Examples of cyclic alkyl groupshaving 3 to 6 carbon atoms include cyclobutyl, cyclopentyl, andcyclohexyl. Furthermore, when a “C₁ to C₁₂ alkyl group that may bebranched or form a cyclic group and/or that may be substituted with ahalogen atom” is referred to, any linear alkyl group having 1 to 12carbon atoms, any branched alkyl group having 3 to 12 carbon atoms, andany cyclic alkyl group having 3 to 12 carbon atoms are included, and ahydrogen atom at any position of these alkyl groups may be substitutedwith a halogen atom. Examples of alkyl groups include n-heptyl,isoheptyl, n-octyl, isooctyl, n-decyl, and n-dodecyl.

The phrase “C₂ to C_(n) alkenyl group that may be branched or form acyclic group” (where n is an integer) includes any linear alkenyl grouphaving 2 to n carbon atoms, any branched alkenyl group having 3 to ncarbon atoms, and any cyclic alkenyl group having 3 to n carbon atoms.Examples of linear alkenyl groups having 2 to 6 carbon atoms includeethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, and 1-hexenyl. Examples of branchedalkenyl groups having 3 to 6 carbon atoms include isopropenyl,1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, and 1-methyl-2-butenyl. Examples of cyclic alkenylgroups having 3 to 6 carbon atoms include cyclobutenyl, cyclopentenyl,and cyclohexenyl. Furthermore, when a “C₂ to C₁₂ alkenyl group that maybe branched or form a cyclic group, and/or that may be substituted witha halogen atom” is referred to, any linear alkenyl group having 2 to 12carbon atoms, any branched alkenyl group having 3 to 12 carbon atoms,and any cyclic alkenyl group having 3 to 12 carbon atoms are included,and a hydrogen atom at any position of these alkenyl groups may besubstituted with a halogen atom. Examples of such alkenyl groups include1-heptenyl, 2-heptenyl, 1-octenyl, 1-decenyl, and 1-dodecenyl.

The phrase “C₂ to C_(n) alkynyl group that may be branched or form acyclic group” (where n is an integer) includes any linear alkynyl grouphaving 2 to n carbon atoms, any branched alkynyl group having 3 to ncarbon atoms, and any cyclic alkynyl group having 3 to n carbon atoms.

Examples of linear alkynyl groups having 2 to 6 carbon atoms includeethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and 1-hexynyl.Examples of branched alkynyl groups having 3 to 6 carbon atoms include1-methyl-2-propynyl. Examples of cyclic alkynyl groups having 3 to 6carbon atoms include cyclopropylethynyl and cyclobutylethynyl.Furthermore, when a “C₂ to C₁₂ alkynyl group that may be branched orform a cyclic group, and/or that may be substituted with a halogen atom”is referred to, any linear alkynyl group having 1 to 12 carbon atoms,any branched alkynyl group having 3 to 12 carbon atoms, and any cyclicalkynyl group having 3 to 12 carbon atoms are included, and a hydrogenatom at any position of these alkynyl groups may be substituted with ahalogen atom. Examples of such alkynyl groups include 1-heptynyl,1-octynyl, 1-decynyl, and 1-dodecynyl.

The phrase “C₁ to C_(n) alkoxy group that may be branched” (where n isan integer) includes alkoxy groups having any linear alkyl groups having1 to n carbon atoms and alkoxy groups having any branched alkyl groupshaving 3 to n carbon atoms. Examples thereof include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, and tert-butyloxy.

In the present invention, examples of an “aralkyl group” include benzyl,phenethyl, naphthylmethyl, 3-phenylpropyl, 2-phenylpropyl,4⁻phenylbutyl, and 2-phenylbutyl.

In the present invention, examples of an “aryl group” include phenyl,naphthyl, anthryl, and phenanthryl.

In the present invention, examples of a “halogen atom” include achlorine atom, a bromine atom, an iodine atom, and a fluorine atom. Inthe present invention, the term “halide anion”_(refers to halogen ions and examples thereof include a chloride ion, a bromide ion, an iodide ion, and a fluoride ion.)

In the present invention, the phrase “C₃ to C_(n) propargyl group orsubstituted propargyl group that may be branched” (where n is aninteger) refers to a propargyl group or any substituted propargyl grouphaving a substituent(s) at position 1 and/or 3 and having 4 to n carbonatoms in total. Examples thereof include 2-propynyl and3-trimethylsilyl-2-propynyl.

Hereinafter, the present invention will be described more specifically.

<Quaternary Ammonium Salt>

The compound of the present invention is a novel quarternary ammoniumsalt, and is preferably pure with respect to its axial asymmetry in theproduction of an optically active α-amino acid derivative and the likedescribed later. The compound of the present invention can berepresented by Formula (I) below:

(whereR² and R^(2′) are each independently:

a hydrogen atom; or

an aryl group, wherein the aryl group may be substituted with at leastone group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom;        R³ and R^(3′) are each independently:

a C₁ to C₅ alkoxy group that may be substituted with a halogen atomand/or an aryl group, and/or that may be branched or form a cyclicgroup;

R⁴ and R^(4′) are each independently a group selected from the groupconsisting of:

(i) _(a) hydrogen atom;

(ii) a halogen atom;

(iii) a C₁ to C₆ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(iv) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(v) a C₂ to C₆ alkynyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(vi) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and

(vii) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom;        R⁷ and R⁸ are each independently a monovalent organic group or        taken together to form a divalent organic group, and        X⁻ is an anion selected from the group consisting of a halide        anion, SCN⁻, HSO₄ ⁻, HF₂ ⁻, CF₃SO₃ ⁻, CH₃—C₆H₄—SO₃ ⁻, and        CH₃SO₃—).

The compound represented by Formula (I) functions usefully as aphase-transfer catalyst for producing, for example, an optically activeα-amino acid or a derivative thereof, and, in particular, anα,α-dialkyl-α-amino acid or a derivative thereof as described later.More specifically, if the compound represented by Formula (I) is used asa phase-transfer catalyst in order to produce an optically activeα-amino acid or a derivative thereof represented by Formula (VI) byalkylating the compound represented by Formula (IV) with the compoundrepresented by Formula (V), the ammonium moiety constituting a cation ofthis compound:

contributes to the reactivity in the alkylation, and the biphenyl moietythat is pure with respect to its axial asymmetry:

contributes to the stereoselectivity of the alkylation reaction.Therefore, in one embodiment, R⁷ and R⁸ of the compound represented byFormula (I) are groups that can retain the catalytic activity andstereoselectivity arising from the ammonium moiety and the biphenylmoiety of the cation, respectively (or inhibit neither catalyticactivity nor selectivity). For example, they can be monovalent organicgroups or divalent organic groups that are inactive compared to theammonium moiety and the biphenyl moiety. In other words, it is notnecessary for R⁷ and R⁸ to be groups which themselves (or itself) haveexcellent reactivity, and they may be any substituent, as long as theydo not adversely affect the reactions involved in the production of theamino acid or derivative thereof as described later. Alternatively, ifthe compound represented by Formula (I) is used as a phase-transfercatalyst for producing an optically active α-amino acid or a derivativethereof as described later, R⁷ and R⁸ in Formula (I) are eachindependently a group selected from the group consisting of:

(i) a C₁ to C₃₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(ii) a C₂ to C₁₂ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iii) a C₂ to C₁₂ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom; and

(iv) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; or        R⁷ and R⁸ are taken together to form a (divalent organic) group        selected from the _(group consisting of:)

—(CH₂)_(m)— (where m is an integer from 2 to 8);

(where R²⁷, R²⁸, R²⁹, R³², R³³ and R³⁴ are each independently a groupselected from the group consisting of;

a hydrogen atom;

a C₁ to C₈ alkyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

a C₂ to C₈ alkenyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

a C₂ to C₈ alkynyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

an aryl group, which may be substituted with a C₁ to C₄ alkyl group thatmay be substituted with a halogen atom, a C₁ to C₃ alkoxy group that maybe substituted with a halogen atom, an aryl group that may besubstituted with a C₁ to C₄ alkyl group that may be substituted with ahalogen atom, a cyano group, a halogen atom, a nitro group, —NR³⁰R³¹(where R³⁰ and R³¹ are each independently a hydrogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom), or a cyclic amino group that is formed by a C₂ to C₈alkylene group; and

an aralkyl group, which has an aryl moiety that may be substituted witha C₁ to C₄ alkyl group that may be substituted with a halogen atom, a C₁to C₃ alkoxy group that may be substituted with a halogen atom, a cyanogroup, a halogen atom, a nitro group, —NR³⁰R³¹ (where R³⁰ and R³¹ areeach independently a hydrogen atom or a C₁ to C₄ alkyl group that may bebranched and that may be substituted with a halogen atom), or a cyclicamino group that is formed by a C₂ to C₈ alkylene group).

In the present invention, it is preferable that R² and R^(2′) of thecompound represented by Formula (I) are both hydrogen atoms.

Alternatively, in the present invention, it is preferable that R² andR^(2′) of the compound represented by Formula (I) are both aryl groups,wherein the aryl group may be substituted with at least one groupselected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

Alternatively, in the present invention, it is preferable that R⁴ andR^(4′) of the compound represented by Formula (I) are both aryl groups,wherein the aryl group may be substituted with at least one groupselected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen, atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

Alternatively, in the present invention, it is preferable that R⁷ and R⁸of the compound represented by Formula (I) are each independently a C₁to C₃₀ alkyl group that may be branched or form a cyclic group and thatmay be substituted with a halogen atom. Alternatively, in thisspecification, it is preferable that R⁷ and R⁸ are each independently aC₁ to C₁₂ alkyl group that may be branched or form a cyclic group andthat may be substituted with a halogen atom, or a C₁₃ to C₃₀ alkyl groupthat may be branched or form a cyclic group and that may be substitutedwith a halogen atom (more preferably, a C₁₃ to C₂₂ alkyl group that maybe branched or form a cyclic group and that may be substituted with ahalogen atom). Alternatively, in this specification, it is preferablethat R⁷ and R⁸ are each independently an alkyl group that may bebranched or form a cyclic group and that may be substituted with ahalogen atom, and it is more preferable that the number of carbon atomsconstituting the alkyl group can be selected from a range in which thelower limit is at least 1, at least 3, at least 13, at least 15, atleast 17, or at least 18, and the upper limit is not more than 30, notmore than 22, not more than 21, not more than 20, not more than 12, notmore than 8, or not more than 4. In particular, in Formula (I), it ispreferable that R⁷ and R⁸ of the compound are both n-butyl groups. Thereason for this is that if a compound represented by Formula (I) havingsuch a substituent group is used as a catalyst (e.g., phase-transfercatalyst) to produce an optically active α-amino acid and a derivativethereof, and preferably an α,α-dialkyl-α-amino acid or a derivativethereof, then the amino acid or a derivative thereof can be producedwith excellent yield and optical purity.

Alternatively, in the present invention, it is preferable that R² andR^(2′) of the compound represented by Formula (I) are the same.

Alternatively, in the present invention, it is preferable that R³ andR^(3′) of the compound represented by Formula (I) are the same.

Alternatively, in the present invention, it is preferable that R⁴ andR^(4′) of the compound represented by Formula (I) are the same.

Alternatively, in the present invention, it is preferable that R⁷ and R⁸of the compound represented by Formula (I) are the same.

<Method of Producing the Quaternary Ammonium Salt>

The quaternary ammonium salt represented by Formula (I) can be producedby reacting a compound represented by Formula (II) below:

with a secondary amine represented by Formula (III) below:

in an organic solvent in the presence of an acid-scavenging agent.

Here, in Formula (II),

R² and R^(2′) are each independently:

a hydrogen atom; or

an aryl group, wherein the aryl group may be substituted with at leastone group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom;        R³ and R^(3′) are each independently:

a C₁ to C₅ alkoxy group that may be substituted with a halogen atomand/or an aryl group, and/or that may be branched or form a cyclicgroup;

R⁴ and R^(4′) are each independently a group selected from the groupconsisting of:

(i) a hydrogen atom;

(ii) a halogen atom;

(iii) a C₁ to C₆ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(iv) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(v) a C₂ to C₆ alkynyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(vi) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and

(vii) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom, and        Z is a halogen atom, and

in Formula (III),

R⁷ and R⁸ are each independently a group selected from the groupconsisting of:

(i) a C₁ to C₃₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom;

(ii) a C₂ to C₁₂ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iii) a C₂ to C₁₂ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom; and

(iv) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; or        R⁷ and R⁸ are taken together to form a (divalent) group selected        from the group consisting of:

—(CH₂)_(m)—(where m is an integer from 2 to 8);

(where R²⁷, R²⁸, R²⁹, R³², R³³ and R³⁴ are each independently a groupselected from the group consisting of:

a hydrogen atom;

a C₁ to C₈ alkyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

a C₂ to C₈ alkenyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

a C₂ to C₈ alkynyl group that may be branched or form a cyclic group,and/or that may be substituted with a halogen atom;

an aryl group, which may be substituted with a C₁ to C₄ alkyl group thatmay be substituted with a halogen atom, a C₁ to C₃ alkoxy group that maybe substituted with a halogen atom, an aryl group that may besubstituted with a C₁ to C₄ alkyl group that may be substituted with ahalogen atom, a cyano group, a halogen atom, a nitro group, —NR³⁰R³¹(where R³⁰ and R³¹ are each independently a hydrogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom), or a cyclic amino group that is formed by a C₂ to C₈alkylene group; and

an aralkyl group, which has an aryl moiety that may be substituted witha C₁ to C₄ alkyl group that may be substituted with a halogen atom, a C₁to C₃ alkoxy group that may be substituted with a halogen atom, a cyanogroup, a halogen atom, a nitro group, —NR³⁰R³¹ (where R³⁰ and R³¹ areeach independently a hydrogen atom or a C₁ to C₄ alkyl group that may bebranched and that may be substituted with a halogen atom), or a cyclicamino group that is formed by a C₂ to C₈ alkylene group).

In the present invention, it is preferable that R² and R^(2′) of thecompound represented by Formula (II) are both hydrogen atoms.

Alternatively, in the present invention, it is preferable that R² andR^(2′) of the compound represented by Formula (II) are both aryl groups,wherein the aryl group may be substituted with at least one groupselected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

Alternatively, in the present invention, it is preferable that R⁴ andR^(4′) of the compound represented by Formula (II) are both aryl groups,wherein the aryl group may be substituted with at least one groupselected from the group consisting of:

a C₁ to C₄ alkyl group that may be branched and that may be substitutedwith a halogen atom,

a C₁ to C₅ alkoxy group that may be branched and that may be substitutedwith a halogen atom,

an aryl group that may be substituted with a halogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom, and

a halogen atom.

Alternatively, in the present invention, it is preferable that R² andR^(2′) of the compound represented by Formula (II) are the same.

Alternatively, in the present invention, it is preferable that R³ andR^(3′) of the compound represented by Formula (II) are the same.

Alternatively, in the present invention, it is preferable that R⁴ andR^(4′) of the compound represented by Formula (II) are the same.

Alternatively, in the present invention, it is preferable that R⁷ and R⁸of the compound represented by Formula (II) are the same.

The compound of Formula (II) used in the present invention can besynthesized, for example, using the following method.

First, a compound (6,6′-dimethylbiphenyl⁻2,2′-diol) represented by thefollowing formula:

is prepared as a starting material. Either the S-form or the R-form ofthe 6,6′-dimethylbiphenyl-2,2′-diol can be used according to theabsolute configuration of the compound (I) of the present invention thatis to be finally produced. The 6,6′-dimethylbiphenyl-2,2′-diol itselfhas a known structure, and can be synthesized, for example, according tothe following reaction scheme. A synthetic method according to thereaction scheme is known, for example, in Japanese Laid-Open. PatentPublication No. 2004-189696.

This 6,6′-dimethylbiphenyl-2,2′-diol is reacted with an alkylating agentin an organic solvent such as acetone in the presence of anacid-scavenging agent (e.g., inorganic bases such as potassiumcarbonate, sodium carbonate, potassium hydrogen carbonate, and sodiumhydrogen carbonate).

Examples of the alkylating agent include a compound represented by R⁴⁰Y(where R⁴⁰ is a C₁ to C₅ alkyl group that may be substituted with ahalogen atom and/or an aryl group, and/or that may be branched or form acyclic group, and Y is a halogen atom or a group represented by thefollowing formula:

(where R⁴² is a C₁ to C₅ alkyl group that may be substituted with ahalogen atom, an alkyl group, or a nitro group, or an aryl group thatmay be substituted with a halogen atom, an alkyl group, or a nitrogroup)). Preferable examples of the alkylating agent include methyliodide and isopropyl iodide. The thus obtained6,6′-dimethyl-2,2′-dialkoxy biphenyl is reacted with a halogenatingagent such as bromine (Br₂) in an organic solvent such asdichloromethane.

The compound thus obtained can be obtained also by halogenating, beforethe reaction with the alkylating agent, the6,6′-dimethylbiphenyl-2,2′-diol at positions 3, 3′, 5 and 5′ usingbromine (Br₂) or the like, and then reacting the resultant with analkylating agent in an organic solvent such as acetone in the presenceof an acid-scavenging agent (e.g., inorganic bases such as potassiumcarbonate, sodium carbonate, potassium hydrogen carbonate, and sodiumhydrogen carbonate).

In this manner, it is possible to obtain a compound represented byFormula (VII) below:

(whereR³ and R^(3′) are each independently:

a C₁ to C₅ alkoxy group that may be substituted with a halogen atomand/or an aryl group, and/or that may be branched or form a cyclicgroup,

Z¹ is a halogen atom, andZ² is a hydrogen atom or a halogen atom).

The compound of Formula (VII) is then subjected to the Suzuki-Miyauracoupling reaction with at least one type of boronic acid derivativerepresented by R⁴—B(OH)₂ or R^(4′)—B(OH)₂ (where R⁴ and R^(4′) are eachindependently the same groups as defined above) in an organic solventsuch as N,N-dimethylformamide (DMF) in the presence of a palladiumcatalyst. Specific examples of the boronic acid derivative include3,4,5-trifluorophenylboronic acid. Subsequently, the methyl group ofthis compound is halogenated by means used ordinarily in the art, sothat it is possible to obtain the compound represented by Formula (II).

On the other hand, in the method for producing the compound representedby Formula (I) of the present invention, a large number of the secondaryamines of Formula (III) are commercially available and can be easilyobtained, or they can be easily produced using known methods.

Examples of the organic solvents used in the reaction process forproducing the compound of Formula (I) of the present invention includenitrile solvents (e.g., acetonitrile, propionitrile), ether solvents(e.g., dioxane, tetrahydrofuran, isopropyl ether, diethyl ether,dimethoxyethane, 2-methoxyethyl ether), alcohol solvents (e.g.,methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol),ester solvents (e.g., ethyl acetate, isopropyl acetate), and amidesolvents (e.g., DMF, N,N-dimethylacetamide). In the present invention,acetonitrile is particularly preferable. Examples of the acid-scavengingagents include inorganic bases, such as potassium carbonate, sodiumcarbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate.

In the reaction, the secondary amine of Formula (III) is used preferablyin 0.5 to 10 equivalents, and more preferably in 0.8 to 3 equivalents,with respect to the compound of Formula (II). The acid-scavenging agentis preferably used in 0.5 to 10 equivalents, and more preferably in 0.8to 5 equivalents, with respect to the compound of Formula (II). Thereaction between the compound of Formula (II) and the secondary amine ofFormula (III) is carried out in a suitable organic solvent in thepresence of the acid-scavenging agent preferably with stirring. Thereaction temperature is preferably from room temperature to the boilingpoint of the organic solvent used, and more preferably the reaction isperformed while heating under reflux. The reaction time is preferably 15minutes to 24 hours, and more preferably 30 minutes to 12 hours. In thiscase, the organic solvent is used in an amount, for example, 5 to 50times or 6 to 30 times the amount of the compound of Formula (II) at avolume (ml)/weight (g) ratio. After the reaction is complete, thereaction mixture is extracted with dichloromethane, dichloroethane,chloroform, or ethyl acetate, and isolation and purification by silicagel column chromatography are performed to obtain the compound ofFormula (I). Alternatively, the reaction mixture may be used withoutfurther treatment as a phase-transfer catalyst in the method forproducing α-amino acid derivatives specifically described later.

The thus obtained compound of Formula (I) in which X⁻ is a halide anionis in a pure form with respect to axial asymmetry, and can be used as aphase-transfer catalyst. Here, “pure with respect to axial asymmetry”means that, in various stereoisomers formed based on the axialasymmetry, one specific isomer is more abundant than the other. Theabundance ratio of the one specific isomer is preferably 90% or more,more preferably 95% or more, and even more preferably 98% or more.

Furthermore, the compound of Formula (I) in which X⁻ is a halide anioncan be converted to a compound in which the halide anion is replaced bySCN⁻, HSO₄ ⁻, HF₂ ⁻, CF₃SO₃ ⁻, CH₃—C₆H₄—SO₃ ⁻ (may be referred to asCH₃-Ph-SO₃ ⁻), or CH₃SO₃ ⁻, for example, according to the followingprocesses.

First, a method for producing the compound of Formula (I) in which X⁻ isSCN⁻ or HSO₄ ⁻ will be described.

The thus obtained compound of Formula (I) in which X⁻ is a halide anionis dissolved in, for example, a suitable second organic solventaccording to the method described in Japanese Laid-Open PatentPublication No. 2002-173492 and the solution is mixed with a saturatedaqueous solution of an alkali metal salt of thiocyanic acid so that thehalide anion of X⁻ is converted to SCN⁻.

Examples of the second organic solvent that can be used in thisconversion include dichloromethane, chloroform, dichloroethane,tetrahydrofuran, methyl t-butyl ether, diisopropyl ether, and ethylacetate. Examples of alkali metal salts of thiocyanic acid includepotassium thiocyanate and sodium thiocyanate.

For example, by bringing the compound of Formula (I) in which X⁻ is ahalide anion into contact with an alkali metal salt of thiocyanic acidin a solution under relatively mild conditions such as at roomtemperature through mixing, the reaction can proceed easily, and thereaction product (that is, the compound of Formula (I) in which X⁻ isSCN⁻) can be obtained in a quantitative yield.

Furthermore, by reacting _(t)he compound of Formula (I) in which X⁻ isSCN⁻ with a concentrated sulfuric acid solution, X⁻ can be easilyconverted from SCN⁻ to HSO₄ ⁻.

The thus obtained compound of Formula (I) in which X⁻ is HSO₄ ⁻ can thenbe further reacted with an alkali metal fluoride (e.g., potassiumfluoride, sodium fluoride or lithium fluoride) to obtain a compoundrepresented by Formula (Ia.):

(where R², R^(2′), R³, R^(3′), R⁴, R^(4′), R⁷ and R⁸ are eachindependently the same as those defined in Formula (I)), which can beused as a catalyst, for example, in a reaction of a silyl enol etherwith a carbonyl compound (aldol reaction).

Examples of the silyl enol ethers used in the aldol reaction include atrialkylsilyl enol ether. A trialkylsilyl enol ether can be prepared inadvance by reacting a chlorosilane, such as trimethylsilyl chloride andtriethylsilyl chloride, with carbonyl compounds (e.g., ketonic carbonylderivatives, such as 2-butanone, 4-penten-2-one, diethyl ketone,acetophenone, propiophenone, butyronaphtone, cyclohexanone, 1-oxoindan,1-tetralone or 2-tetralone) in the presence of a base.

In addition to the above-mentioned carbonyl compounds (theabove-described ketonic carbonyl derivatives), which function asprecursors of the silyl enol ethers, examples of the carbonyl compoundsthat can be used to prepare silyl enol ethers for the aldol reactioninclude aldehyde compounds, such as acetylaldehyde, propionaldehyde,butylaldehyde, isobutylaldehyde, isovaleraldehyde, capronaldehyde,dodecylaldehyde, palmitinaldehyde, stearinaldehyde, acrolein,crotonaldehyde, cyclohexanecarbaldehyde, benzaldehyde, anisaldehyde,nicotinaldehyde, cinnamaldehyde, α-naphthaldehyde, and β-naphthaldehyde.

With respect to such a silyl enol ether and such a carbonyl compound,the compound represented by Formula (Ia) is used as a catalyst in thealdol reaction to control the stereoselectivity of the reaction.

Next, a method for producing the compound of Formula (I) in which X⁻ isHF₂ ⁻, CF₃SO₃ ⁻, CH₃-Ph-SO₃ ⁻, or CH₃SO₃ ⁻ will be described.

The compound of Formula (I) obtained in the above-described manner inwhich X⁻ is a halide anion is brought in contact with an ion-exchangeresin to produce a first intermediate.

The ion-exchange resin can be freely selected by those skilled in theart. Specific examples of the ion-exchange resin that can be usedinclude Amberlyst A26 (OH) (manufactured by ORGANO CORPORATION).

The compound of Formula (I) in which X⁻ is a halide anion and theion-exchange resin can be brought in contact by dissolving the compoundof Formula (I) in which X⁻ is a halide anion in a suitable third solventand passing this solution through a column filled with the ion-exchangeresin. An alcohol solvent is preferable as the third solvent that can beused for such a contact. Specific examples of alcohol solvents includemethyl alcohol, ethyl alcohol, isopropyl alcohol, and normal propylalcohol, but are not limited thereto.

There is no specific limitation on the amount of the compound of Formula(I) in which X⁻ is a halide anion and the amount of the third solventused for such contact, and they can be appropriately set by thoseskilled in the art.

Thus, the first intermediate is produced.

Next, the first intermediate thus obtained is treated with an acidsolution (e.g., a hydrogen fluoride aqueous solution, a methanesulfonicacid solution, a toluenesulfonic acid solution, or atrifluoromethanesulfonic acid solution) preferably without removing thesolvent described above.

There is no specific limitation on the amount of hydrogen fluorideaqueous solution or sulfonic acid solution used in the presentinvention. In view of increasing the productivity, it is preferable thatthe amount is chosen so that an equal or greater amount of hydrogenfluoride or sulfonic acid is reacted with the compound of Formula (I)used above in which X⁻ is a halide anion. Thus, a compound representedby any of Formulae (Ib) to (Ie):

in which the quaternary ammonium moiety is liberated from the firstintermediate, and X⁻ is further converted from a halide anion to HF₂ ⁻,CF₃SO₃ ⁻, CH₃-Ph-SO₃ ⁻, or CH₃SO₃ ⁻ can be precipitated from thesolution.

The compounds of Formulae (Ib) to (Ie) can be easily isolated byremoving the solvent using means employed ordinarily by those skilled inthe art.

The thus obtained compounds of Formulae (Ib) to (Ie), and particularlythe compound of Formula (Ib), can also be utilized as a catalyst forproducing a nitroalcohol diastereo- and enantioselectively.

<Method for Producing cc-Amino Acid Derivatives>

Next, a method for producing α-amino acid derivatives using thequaternary ammonium compound of the present invention represented byFormula (I) as a phase-transfer catalyst will be described.

An α-amino acid derivative represented by Formula (VI):

(whereR¹⁴ and R¹⁵ are each independently:

(i) a hydrogen atom; or

(ii) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom,

with the proviso that the case where R¹⁴ and R¹⁵ are both hydrogen atomsis excluded;

R¹⁶ is a group selected from the group consisting of:

(i) a hydrogen atom;

(ii) a C₁ to C₁₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom, wherein the alkyl groupmay be substituted with a C₁ to C₅ alkoxy group that may be branched andthat may be substituted with a halogen atom;

(iii) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iv) a C₂ to C₆ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(v) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and a halogen atom; and

(vi) an aryl group, wherein the aryl group may be substituted with atleast one group selected from the group consisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom;        R¹⁷ is a C₁ to C₈ alkyl group that may be branched or form a        cyclic group;        R¹⁸ is a group selected from the group consisting of:

(i) a C₁ to C₁₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom, wherein the alkyl groupmay be substituted with a C₁ to C₅ alkoxy group that may be branched andthat may be substituted with a halogen atom;

(ii) a C₂ to C₆ alkenyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iii) a C₂ to C₆ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom;

(iv) an aralkyl group, wherein the aryl moiety constituting the aralkylgroup may be substituted with at least one group selected from the groupconsisting of:

-   -   a C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom,    -   a C₁ to C₅ alkoxy group that may be branched and that may be        substituted with a halogen atom,    -   an aryl group that may be substituted with a halogen atom or a        C₁ to C₄ alkyl group that may be branched and that may be        substituted with a halogen atom, and    -   a halogen atom; and

(v) a C₃ to C₉ propargyl group or substituted propargyl group that maybe branched and that may be substituted with a halogen atom; and *indicates a newly produced asymmetric center) can be producedstereoselectively through the process of alkylating the compoundrepresented by Formula (IV):

(where R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are the same as those defined in Formula(VI))with a compound of Formula (V):

R¹⁸—W   (V)

(where R¹⁸ is the same as that defined in Formula (VI), and W is afunctional group having a leaving ability) using the compoundrepresented by Formula (I) as a phase-transfer catalyst in a medium inthe presence of an inorganic base.

Examples of the medium used in the alkylation process include benzene,toluene, xylene, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane,ethyl acetate, isopropyl acetate, cyclopentyl methyl ether, and methylt-butyl ether. Alternatively, the medium may also be a biphasic onecontaining water and a medium immiscible with water. The medium can beused preferably 0.5 to 30 times, and more preferably 1 to 25 times theamounts of the compound of Formula (IV) at a ratio of volume (ml)/weight(g).

Examples of the inorganic base used in the alkylation process includelithium hydroxide, sodium hydroxide, potassium hydroxide, calciumhydroxide, rubidium hydroxide, and cesium hydroxide. The inorganic basecan be used preferably in 0.5 to 100 equivalents, and more preferably in0.8 to 40 equivalents, with respect to the compound of Formula (IV).

In the alkylation process, an inorganic base may be used in the form ofan aqueous inorganic-base solution. In the case where an inorganic baseis used in the form of an aqueous inorganic-base solution, the upperlimit of the inorganic base that can be contained in the aqueousinorganic-base solution is preferably 280 equivalents or less, morepreferably 150 equivalents or less, and even more preferably 56equivalents or less, with respect to the compound of Formula (IV). Thelower limit of the inorganic base that can be contained in the aqueousinorganic-base solution is preferably 0.5 equivalents or more, morepreferably 0.8 equivalents or more, and even more preferably 0.9equivalents or more, with respect to the compound of Formula (IV). Theaqueous inorganic-base solution may be used preferably in 5 w/w % to 70w/w %, and more preferably in 10 w/w % to 60 w/w %.

The volume ratio between the medium and the aqueous inorganic-basesolution is preferably a medium volume (ml)/aqueous inorganic-basesolution (ml) ratio of 7/1 to 1/5, more preferably 5/1 to 1/3, and evenmore preferably 4/1 to 1/1.

In the alkylation process, the compound of Formula (V) is usedpreferably in 0.5 to 10 equivalents, more preferably in 0.7 to 6equivalents, and even more preferably in 0.9 to 5 equivalents, withrespect to the compound of Formula (IV). The compound of Formula (I) isused as a phase-transfer catalyst preferably in amounts at a lower limitof not less than 0.0001 mol % and more preferably not less than 0.0005mol %, and at an upper limit of preferably not more than 10 mol %, morepreferably not more than 2 mol %, even more preferably not more than 1mol %, and yet even more preferably not more than 0.5 mol %, withrespect to 1 mol of the compound of Formula (IV). Thus, thephase-transfer catalyst used in the present invention has extremely highactivity, and therefore by using the catalyst only in a very smallamount with respect to 1 mol of the compound of Formula (IV), thedesired optically active α-amino acids and derivatives thereof can beobtained.

Furthermore, in the present invention, in addition to the asymmetricalphase-transfer catalyst represented by Formula (I), an achiralquaternary ammonium salt, such as tetrabutylammonium bromide (TBAB), canalso be used together. For example, TBAB functions as a cocatalyst inthe reaction system of the present invention to improve the yield ofα-amino acids and derivatives thereof, and also allows the amount of theasymmetrical phase-transfer catalyst represented by Formula (I) that isused in the present invention to be further reduced. The amount of TBABthat can be used in the present invention is preferably 0.005 mol % to 1mol %, and more preferably 0.01 mol % to 0.8 mol %, with respect to 1mol of the compound of Formula (IV).

The alkylation process is performed at suitable temperatures between−70° C. and room temperature, preferably between −20° _(C. and) 20° C.,in air, under a nitrogen atmosphere, or under an argon atmosphere. Thisprocess can be performed with stirring for a suitable period until thealkylation reaction has sufficiently proceeded. The reaction time ispreferably 30 minutes to 48 hours, and more preferably 1 hour to 24hours.

When the aqueous inorganic-base solution is used in the alkylationprocess, it is preferable to split the process into multiple operations,as described below.

In other words, at first, the compound of Formula (IV), thephase-transfer catalyst of Formula (I), and the compound of Formula (V)are each added to the medium to prepare a mixture. At this time, it ispreferable to sufficiently stir the mixture with cooling using, forexample, ice or ice-salt. To the cooled mixture is then added theaqueous inorganic-base solution to alkylate the compound of Formula(IV). The temperatures set to cool the mixture are preferably between−20° C. and 20° C., more preferably between −15° C. and 15° C., and evenmore preferably between −10° C. and 10° C.

According to the method of the present invention using the compound ofFormula (I) as described above, the optically active compound of Formula(VI) can be obtained in a high yield and high optical purity. Here, highoptical purity refers to an optical purity of preferably at least 80%ee, more preferably at least 85% ee, yet more preferably at least 90%ee, and even more preferably at least 95% ee.

<Method for Producing α-Amino Acid>

In another aspect of the present invention, a method for producingoptically active α-amino acids is provided.

In the present invention, an optically active α-amino acid can beproduced by performing, for example, either one of the followingprocedures, using the optically active compounds of Formula (VI)(optically active α-amino acid derivatives) obtained by the methoddescribed above.

In the first method, first, the imino group (R¹⁴R¹⁵C═N—) moietyconstituting the optically active compound of Formula (VI) (opticallyactive α-amino acid derivative) obtained by the above-described methodis first hydrolyzed under acidic conditions (imine acidic-hydrolysisprocess). Examples of the acids used in the imine acidic-hydrolysisprocess include inorganic acids (e.g., hydrochloric acid or phosphoricacid) and organic acids including tribasic acids (e.g., acetic acid,citric acid, p-toluenesulfonic acid). More specifically, the imineacidic-hydrolysis process proceeds by treating the compound of Formula(VI) in a suitable medium (e.g., tetrahydrofuran or toluene) at asuitable temperature (e.g., room temperature) using an aqueous solutionof the acid. As a result, an ester derivative of amino acid in which theterminal amino group is liberated can be obtained as an imineacidic-hydrolysis product.

Next, if necessary, the ester derivative of the amino acid(acidic-hydrolysis product) obtained above is subjected to a hydrolysisreaction under conditions more acidic than the imine acidic-hydrolysisor under basic conditions. Thus, a desired amino acid in which theterminal of the acidic-hydrolysis product (i.e., the ester group(—CO₂R¹⁷) constituting the imine acidic-hydrolysis product) has become acarboxylic acid can be obtained.

Alternatively, in the second method, a process in the opposite orderrelative to that of the method described above is adopted. That is tosay, the ester group (—CO₂R¹⁷) constituting the optically activecompound of Formula (VI) (optically active α-amino acid derivative)obtained by the alkylation reaction described above is first hydrolyzedunder basic conditions (ester basic-hydrolysis process). An aqueousalkali solution, such as aqueous sodium hydroxide solution, can be usedin this ester basic-hydrolysis process. By such hydrolysis, an esterbasic-hydrolysis product in which the terminal of the compound ofFormula (VI) (that is, the ester group (—CO₂R¹⁷) constituting thecompound of Formula (VI)) has become a carboxylic acid can be obtained.

Next, the imino group (R¹⁴R¹⁵C═N—) moiety of the above-obtainedbasic-hydrolysis product is hydrolyzed under acidic conditions (imineacidic-hydrolysis process). Examples of the acids used in the imineacidic-hydrolysis process include inorganic acids (e.g., hydrochloricacid, phosphoric acid, sulfuric acid) and organic acids includingtribasic acids (e.g., acetic acid, citric acid). More specifically, theimine acidic-hydrolysis process proceeds by treating the esterbasic-hydrolysis product in a suitable medium (e.g., tetrahydrofuran ortoluene) at a suitable temperature (e.g., room temperature) using anaqueous solution of the acid described above. As a result, a desiredamino acid in which the terminal amino group is liberated can beobtained.

In the present invention, in the case where an amino acid is producedfrom the compound of Formula (VI), either the first method or the secondmethod may be used, and either method can be selected arbitrarily bythose skilled in the art according to the specific structure of theamino acid to be actually produced and other relevant productionconditions.

Thus, it is possible to produce a desired optically active α-amino acid,efficiently and as one chooses, without limitations on its structure.

EXAMPLES

Hereinafter, the present invention will be specifically described by wayof examples, but is not limited thereto.

In the following examples, unless described otherwise, measurements werecarried out under the following conditions.

The infrared (IR) spectrum was recorded using an IR Prestage-21spectrometer manufactured by Shimadzu Corporation.

The ¹H and ¹³C NMR spectra were measured using a JEOL JUM-FX400 NMRapparatus manufactured by JEOL Ltd. (400 MHz in ¹H NMR and 100 MHz in¹³C NMR) at room temperature. Unless described otherwise, calibrationwas performed using the center lines of Si(CH₃)₄ (δ=0 ppm) and CDCl₃triplet (δ=77 ppm) as the internal standard. The multiplicity wasindicated using the following symbols: s=singlet; d=doublet; t=triplet;q=quartet; m=multiplet; and br=broad.

High-performance liquid chromatography (HPLC) was performed with aShimadzu 10A instrument manufactured by Shimadzu Corporation using aDaicel CHIRALPAK OD or OD-H 4.6 mm×25 mm column manufactured by DAICELCHEMICAL INDUSTRIES, LTD.

High resolution mass spectrometry (HRMS) was performed using a BRUKERmicrOTOF focus-KR manufactured by Bruker.

The optical rotation was measured using a JASCO DIP-1000 digitalpolarimeter manufactured by JASCO Corporation.

All reactions were monitored by thin layer chromatography (TLC). In theTLC, a silica gel plate (thickness: 0.25 mm, 60E-254) manufactured byMerck was used, and visualization was performed using 254 nm UV light ora dye such as KMnO₄, phosphomolybdic acid (PMA) and CeSO₄. The productwas purified by flash column chromatography using silica gel 60(1.09386.9025 manufactured by Merck, 230 to 400 mesh).

Example 1 Synthesis of (S)-2,2′-dimethoxy-6,6′-dimethylbutyl phenyl (6)

Methyl iodide (0.52 mL, 8.3 mmol) and K₂CO₃ (0.57 mg, 4.2 mmol) wereadded to a solution of (S)-6,6′-dimethylbiphenyl-2,2′-diol (5) (89 mg,0.42 mmol) in acetone (5.0 ml). After being stirred at room temperaturefor 5 hours, the obtained mixture was filtered through a celite pad withethyl acetate. The filtrate was concentrated to obtain a residue. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (6) (105 mg, quantitative).

The physical property data of the obtained compound (6) is shown inTable 1.

TABLE 1 Physical property data of compound (6) [α]³² _(D) −38 (c 0.60,CHCl₃); ¹H NMR δ 7.21 (t, J = 8 Hz, 2 H), 6.89 (d, J = 8 Hz, 2 H), 6.79(d, J = 8 Hz, 2 H), 3.65 (s, 6 H), 1.93 (s, 6 H); ¹³C NMR δ 156.9,138.1, 127.8, 126.1, 122.1, 108.2, 55.6, 19.5; IR (neat) 2941, 1579,1466, 1252, 1080, 777, 743 cm⁻¹; HRMS (ESI) Calculated for C₁₆H₁₉O₂243.1380 ([M + H⁺]), Found: 243.1383 ([M + H⁺]).

Example 2 Synthesis of(5)-3,3′-dibromo-6,6′-dimethoxy-2,2′-dimethyl-biphenyl (7)

Acetic acid (0.005 mL, 0.083 mmol) and Br₂ (0.45 mL, 0.87 mmol) weresuccessively added to a solution of (S)-2,2′-dimethoxy-6,6′-dimethylbiphenyl (6) (105 mg, 0.415 mmol) obtained in Example 1 inCH₂Cl₂ (4.0 mL). The obtained solution was stirred at room temperaturefor 1 hour, and poured into an ice-cold saturated NaHCO₃ aqueoussolution. The organic phase was separated, and the aqueous phase wasextracted twice with ethyl acetate. The combined extract was dried overNa₂SO₄ and concentrated to obtain a residual oil. The oil was purifiedby silica gel column chromatography (hexane/ethyl acetate) to give thetitle compound (7) (161 mg, 97%).

The physical property data of the obtained compound. (7) is shown inTable 2.

TABLE 2 Physical property data of compound (7) [α]³² _(D) −36 (c 0.68,CHCl₃); ¹H NMR δ 7.49 (d, J = 9 Hz, 2 H), 6.68 (d, J = 8 Hz, 2 H), 3.63(s, 6 H), 1.99 (s, 6 H); ¹³C NMR δ 156.0, 137.3, 131.9, 127.6, 116.3,109.9, 55.8, 20.0; IR (neat) 2934, 2359, 1566, 146, 1429, 1281, 1254,1080, 1230, 799 cm⁻¹; HRMS (ESI) Calculated for C₁₆H₁₆Br₂O₂ 397.9512([M⁺]), Found: 397.9500 ([M⁺]).

Example 3 Synthesis of(S)-3,3′-di(3,4,5-trifluorophenyl)-6,6′-dimethoxy-2,2′-dimethylbiphenyl(8)

First, 3,4,5-trifluorophenylboronic acid (868 mg, 5.50 mmol), Pd(OAc)₂(62 mg, 0.28 mmol), P(o-tolyl)₃ (P(o-Tol)₃: 335 mg, 1.10 mmol), andK₃PO₄-nH₂O (3.93 g, 13.8 mmol) were successively added to a solution of(S)-3,3′-dibromo-6,6′-dimethoxy-2,2′-dimethylbiphenyl (7) (550 mg, 1.37mmol) obtained in Example 2 in dry DMF (15 mL). After being refluxedunder an argon atmosphere overnight, the obtained mixture was filteredthrough a celite pad with diethyl ether. The filtrate was poured into amixture of H₂O and diethyl ether with vigorous stirring. The organicphase was separated, and the aqueous phase was extracted twice withdiethyl ether. The combined extract was dried over Na₂SO₄ andconcentrated to obtain a residue. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate) to give the title compound(8) in a quantitative yield.

The physical property data of the obtained compound (8) is shown inTable 3.

TABLE 3 Physical property data of compound (8) [α]³² _(D) −8 (c 0.43,CHCl₃); ¹H NMR δ 7.18 (d, J = 8 Hz, 2 H), 6.97 (t, J = 8 8 Hz, 4 H),6.90 (d, J = 8 Hz, 2 H), 3.76 (s, 6 H), 1.86 (s, 6 H); ¹³C NMR δ 156.7,150.7 (ddd, J_(C-F) = 250, 10, 4 Hz), 138.6 (dt, J_(C-F) = 251, 5 Hz),138.4 (dt, J_(C-F) = 8, 5 Hz), 135.2, 132.2, 129.6, 126.9, 113.7 (dd,J_(C-F) = 16, 6 Hz), 108.4, 55.7, 17.4; IR (neat) 2940, 1614, 1516,1477, 1261, 1244, 1084, 1042, 806, 754 cm⁻¹; HRMS (ESI) Calculated forC₂₈H₂₀F₆O₂ 502.1362 ([M⁺]), Found: 502.1381 ([M⁺]).

Example 4 Synthesis of(S)-2,2′-bis(bromomethyl)-6,6′-dimethoxy-3,3′-di(3,4,5-trifluorophenyl)biphenyl (9)

N-Bromosuccinimide (611 mg, 3.43 mmol) and 2,2′-azobisisobutyronitrile(AIBN) (23 mg, 0.14 mmol) were successively added to a solution of(S)-3,3′-di(3,4,5-trifluorophenyl)-6,6′-dimethoxy-2,2′-dimethylbiphenyl(8) (690 mg, 1.37 mmol) obtained in Example 3 in benzene (10 mL). Afterbeing refluxed for 1.5 hours, the mixture was cooled to room temperatureand filtered through a celite pad using diethyl ether. The filtrate wasconcentrated to obtain a residue. The residue was purified by silica gelcolumn chromatography (hexane/diethyl ether) to give the title compound(9) (820 mg, 91%).

The physical property data of the obtained compound (9) is shown inTable 4.

TABLE 4 Physical property data of compound (9) [α]³³ _(D) +51 (c 0.40,CHCl₃); ¹H NMR δ 7.26 (d, J = 9 Hz, 2 H), 7.16 (d, J = 8 Hz, 4 H), 7.04(d, J = 8 Hz, 2 H), 4.08 (s, 4 H), 3.77 (s, 6 H); ¹³C NMR δ 157.0, 150.7(ddd, J_(C-F) = 251, 10, 5 Hz), 139.1 (dt, J_(C-F) = 253, 15 Hz), 136.4(dt, J_(C-F) = 8, 5 Hz), 132.8, 131.3, 125.5, 113.8 (dd, J_(C-F) = 16, 6Hz), 111.2, 55.7, 30.1; IR (neat) 2940, 1614, 1526, 1477, 1435, 1271,1043, 816, 758 cm⁻¹; HRMS (ESI) Calculated for C₂₈H₁₈Br₂F₆O₂ 657.9572([M⁺]), Found: 657.9571 ([M⁺]).

Example 5 Synthesis of chiral ammonium salt ((S)-4a)

Bu₂NH (0.74 mL, 0.43 mmol) and K₂CO₃ (0.60 mg, 4.4 mmol) were added to asolution of(S)-2,2′-bis(bromomethyl)-6,6′-dimethoxy-3,3′-di(3,4,5-trifluorophenyl)biphenyl (9) (316 mg, 0.48 mmol) obtained in Example 4 in acetonitrile(5 mL). After being stirred at 85° C. overnight, the obtained mixturewas cooled to room temperature and filtered through a celite pad usingCH₂Cl₂. The filtrate was concentrated to obtain a residue. The residuewas purified by silica gel column chromatography (CH₂Cl₂/CH₃OH) to givethe title compound chiral ammonium salt ((S)-4a) in the form of a whitesolid (290 mg, 94%).

The physical property data of the obtained chiral ammonium salt ((S)-4a)is shown in Table 5.

TABLE 5 Physical property data of chiral ammonium salt ((S)-4a) [α]³²_(D) −63 (c 0.37, CHCl₃); ¹H NMR δ 7.41 (d, J = 9 Hz, 2 H), 7.23 (d, J =9 Hz, 2 H), 7.14 (br s, 4 H), 4.74 (d, J = 14 Hz, 2 H), 3.90 (s, 6 H),3.66 (d, J = 14 Hz, 2 H), 3.18 (t, J = 13 Hz, 2 H), 2.65-2.80 (m, 2 H),0.90-1.18 (m, 6 H), 0.73 (t, J = 7 Hz, 6 H), 0.20- -0.38 (m, 2 H); ¹³CNMR δ 156.9, 151.6-152.4 (m), 149.2- 149.8(m), 139.3 (dt, J_(C-F) = 255,16 Hz), 134.8 (dt, J_(C-F) = 16, 4 Hz), 132.5, 131.9, 126.3, 125.0,113.5- 115.5 (m), 113.3, 57.1, 56.9, 55.8, 24.2, 19.0, 12.9; IR (neat)3400, 2965, 1614, 1528, 1489, 1287, 1045, 733 cm⁻¹; HRMS (ESI)Calculated for C₃₆H₃₆F₆NO₂ 628.2645 ([M⁺]), Found: 628.2642 ([M⁺]).

Example 6 Synthesis of chiral ammonium salt ((S)-4b)

(S)-2,2′-Diisopropoxy-6,6′-dimethylbutyl phenyl was synthesized in thesame manner as in Example 1, except that isopropyl iodide (0.81 mL, 8.3mmol) was used instead of the methyl iodide used in Example 1. Then,treatment as in Examples 2 to 5 was performed using the(S)-2,2′-diisopropoxy-6,6′-dimethylbutyl phenyl instead of the compound(6) obtained in Example 1, to give the following chiral ammonium salt((S)-4b) (250 mg, 78%).

The physical property data of the obtained chiral ammonium salt ((S)-4b)is shown in Table 6.

TABLE 6 Physical property data of chiral ammonium salt ((S)-4b) ¹H NMR δ7.35 (d, J = 9 Hz, 2 H), 7.14 (d, J = 9 Hz, 2 H), 4.76 (d, J = 14 Hz, 2H), 4.56 (m, 2 H), 3.60 (d, J = 14 Hz, 2 H), 3.23 (t, J = 13 Hz, 2 H),2.65-2.76 (m, 2H), 1.40 (d, J = 6 Hz, 6 H), 1.22 (d, J = 6 Hz, 6 H),0.94-1.10 (m, 6 H), 0.73 (t, J = 7 Hz, 6 H), 0.29 (m, 2 H)

Example 7 Synthesis of(S)-3,3′,5,5′-tetrabromo-6,6′-dimethylbiphenyl-2,2′-diol (10)

Acetic acid (0.006 mL, 0.10 mmol) and Br₂ (0.11 mL, 2.10 mmol) weresuccessively added to a solution of (S)-6,6′-dimethylbiphenyl-2,2′-diol(5) (110 mg, 0.51 mmol) in CH₂Cl₂ (5.0 mL). After being stirred at roomtemperature for 40 minutes, the obtained solution was poured into amixture of H₂O and CH₂Cl₂ with vigorous stirring. The organic layer wasseparated, and the aqueous layer was extracted twice with CH₂Cl₂. Thecombined extract was dried over Na₂SO₄ and concentrated to obtain aresidual solid. The solid was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (10)(236 mg, 87%).

The physical property data of the obtained compound (10) is shown inTable 7.

TABLE 7 Physical property data of compound (10) [α]³² _(D) −38 (c 0.50,CHCl₃); ¹H NMR δ 7.75 (s, 2 H), 5.35 (s, 2 H), 2.03 (s, 6 H); ¹³C NMR δ149.0, 137.8, 134.7, 124.5, 116.1, 107.9, 20.0; IR (neat) 3501, 1425,1287, 1211, 1061, 1032, 758, 675 cm⁻¹; HRMS (ESI) Calculated forC₁₄H₉Br₄O₂ 524.7331 ([M − H]⁻), Found: 524.7337 ([M − H]⁻).

Example 8 Synthesis of(S)-3,3′,5,5′-tetrabromo-2,2′-dimethoxy-6,6′-dimethylbiphenyl (11)

Methyl iodide (0.56 mL, 8.9 mmol) and K₂CO₃ (0.62 mg, 4.45 mmol) wereadded to a solution of (S)-3,3′,5,5′-tetrabromo-6,6′-dimethylbiphenyl-2,2′-diol (10) (236 mg, 0.45 mmol) obtained in Example7 in acetone (10 mL). After being stirred at room temperature for 2hours, the obtained mixture was filtered through a celite pad usingethyl acetate. The filtrate was concentrated to obtain a residue. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate) to give the title compound (11) (246 mg, 98%).

The physical property data of the obtained compound (11) is shown inTable 8.

TABLE 8 Physical property data of compound (11) [α]³² _(D) +7 (c 0.64,CHCl₃); ¹H NMR δ 7.84 (s, 2 H), 3.54 (s, 6 H), 2.03 (s, 6 H); ¹³C NMR δ153.8, 136.8, 136.0, 133.6, 120.3, 115.0, 60.5, 20.5; IR (neat) 2938,1452, 1406, 1350, 1260, 1063, 930, 866 cm⁻¹; HRMS (ESI) Calculated forC₁₆H₁₄Br₄O₂ 553.7722 ([M⁺]), Found: 553.7718 ([M⁺]).

Example 9 Synthesis of (S)-3,3′,5,5′-tetra(3,4,5-trifluorophenyl)-2,2′-dimethoxy-6,6′-dimethylbiphenyl (12)

First, 3,4,5-trifluorophenylboronic acid (718 mg, 4.55 mmol), Pd(OAc)₂(34 mg, 0.15 mmol), P(o-Tol)₃ (185 mg, 0.61 mmol) and K₃PO₄-nH₂O (2.17g, 7.58 mmol) were successively added to a solution of(S)-3,3′,5,5′-tetrabromo-2,2′-dimethoxy-6,6′-dimethylbiphenyl (11) (423mg, 0.76 mmol) obtained in Example 8 in dry DMF (10 mL). After beingrefluxed under an argon atmosphere for 20 hours, the obtained mixturewas filtered through a celite pad using diethyl ether. The filtrate waspoured into a mixture of H₂O and diethyl ether with vigorous stirring.The combined extract was dried over Na₂SO₄ and concentrated to obtain aresidue. The residue was purified by silica gel column chromatography(hexane/diethyl ether) to give the title compound (12) (377 mg, 65%).

The physical property data of the obtained compound (12) is shown inTable 9.

TABLE 9 Physical property data of compound (12) [α]³⁴ _(D) +17 (c 0.15,CHCl₃); ¹H NMR δ 7.28 (d, J = 8 Hz, 2 H), 7.29 (d, J = 9 Hz, 2 H), 7.20(s, 2 H), 7.00 (d, J = 8 Hz, 2 H), 6.98 (d, J = 8 Hz, 2 H), 3.31 (s, 6H), 1.98 (s, 6 H); ¹³C NMR δ 154.8, 151.1 (ddd, J_(C-F) = 251, 10, 4Hz), 138.8 (ddt, J_(C-F) = 254, 16, 4 Hz), 136.1, 135.65, 135.56 (ddt,J_(C-F) = 316, 8, 5 Hz), 132.8, 131.2, 129.4, 113.4 (ddd, J_(C-F) = 58,16, 6 Hz), 60.4, 18.1; IR (neat) 2930, 2359, 1614, 1526, 1470, 1418,1395, 1258, 1098, 860, 732 cm⁻¹; HRMS (ESI) Calculated for C₄₀H₂₂F₁₂O₂762.1423 ([M⁺]), Found: 762.1424([M⁺]).

Example 10 Synthesis of chiral ammonium salt ((S)-5)

N-Bromosuccinimide (203 mg, 1.14 mmol) and 2,2′-azobisisobutyronitrile(AIBN) (8 mg, 0.049 mmol) were successively added to a solution of(S)-3,3′,5,5′-tetra(3,4,5-trifluorophenyl)-2,2′-dimethoxy-6,6′-dimethylbiphenyl(12) (377 mg, 0.49 mmol) obtained in Example 9 in benzene (5.0 mL).After being refluxed for 30 min, the mixture was cooled to roomtemperature and filtered through a celite pad using diethyl ether. Thefiltrate was concentrated to obtain the compound (13) as a residualsolid. This compound was used in the following reaction without furtherpurification.

Bu₂NH (0.051 mL, 0.30 mmol) and K₂CO₃ (410 mg, 2.96 mmol) were added toa solution of the thus obtained crude product (compound (13)) inacetonitrile (5 mL). After being stirred at 95° C. for 10 hours, theobtained mixture was cooled to room temperature and filtered through acelite pad using CH₂Cl₂. The filtrate was concentrated to obtain aresidue. The residue was purified by silica gel chromatography(CH₂Cl₂/methanol) to give the chiral ammonium salt ((S)-5) in the formof a white solid (254 mg, 53% after two processes).

The physical property data of the obtained chiral ammonium salt ((S)-5)is shown in Table 10.

TABLE 10 Physical property data of chiral ammonium salt ((S)-5) [α]³⁴_(D) −34 (c 0.48, CHCl₃); ¹H NMR δ 7.20-7.60 (m, 10 H), 4.73 (d, J = 14Hz, 2 H), 4.05 (d, J = 14 Hz, 2 H), 3.41 (s, 6 H), 3.08 (t, J = 12 Hz, 1H), 2.85 (t, J = 12 Hz, 2 H), 0.85-1.20 (m, 6 H), 0.73 (t, J = 7 Hz, 6H), 0.30 (br s, 2 H); ¹³C NMR δ 156.0, 151.2 (ddd, J_(C-F) = 251, 9, 3Hz), 139.8 (dq, J_(C-F) = 256, 15 Hz), 136.6, 134.7, 134.1-134.6 (m),133.8, 132.5-133.0 (m), 113.6 (dd, J_(C-F) = 16, 6 Hz), 61.8, 57.5,24.4, 19.4, 13.2; IR (neat) 3404, 2965, 2357, 1616, 1528, 1472, 1398,1260, 1242, 1045, 862 cm⁻¹; HRMS (ESI) Calculated for C₄₈H₃₈F₁₂NO₂880.2705 ([M⁺]), Found: 880.2703 ([M⁺]).

Example 11 Confirmation of α-benzylation of glycine (A1)

A mixture of the chiral ammonium salt ((S)-4a) (1 mol %; phase-transfercatalyst) obtained in Example 5 and benzyl bromide (3 equivalents) asthe compound represented by R¹⁸—W in the above formula was added to amixture of 50% KOH aqueous solution (1 mL) and a toluene solution (1.5mL) of N-(biphenylmethylene)glycine tert-butyl ester (20) (88.6 mg, 0.3mmol), and the resultant was stirred vigorously under an argonatmosphere at 0° C. for 5 hours. Completion of the reaction wasconfirmed by TLC, and then the mixture was poured into water andextracted with ether. The organic extract was washed with brine anddried over Na₂SO₄. The solvent was evaporated under reduced pressure,and then the residual oil was purified by silica gel columnchromatography (ether/hexane= 1/10 as the eluent) to give thecorresponding compound (21) ((R)-tert-butylN-(diphenylmethylene)phenylalanine) (yield 96%). The optical purity ofthe compound (21) obtained in this example was analyzed by HPLC (DaicelChiralcel OD, eluent: hexane/2-propanol=100/1, flow rate: 0.5 mL/min,retention time: (R)-form=14.8 min and (S)-form=28.2 min). The opticalpurity of the compound (21) obtained in this example is shown in Table11.

Example 12 Confirmation of α-benzylation of glycine (A2)

The compound (21) was obtained in a quantitative yield in the samemanner as in Example 11, except that the reaction temperature was set toroom temperature instead of 0° C., and the reaction time was set to 3hours instead of 5 hours. The optical purity of the compound (21)obtained in this example is shown in Table 11.

Example 13 Confirmation of α-benzylation of glycine (A3)

The compound (21) was obtained (yield 95%) in the same manner as inExample 11, except that the chiral ammonium salt ((S)-4b) (1 mol %)obtained in Example 6 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, and thereaction time was set to 4 hours instead of 5 hours. The optical purityof the compound (21) obtained in this example is shown in Table 11.

Example 14 Confirmation of α-benzylation of glycine (A4)

The compound (21) was obtained (yield 92%) in the same manner as inExample 11, except that the chiral ammonium salt ((S)-4b) (1 mol %)obtained in Example 6 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, thereaction temperature was set to room temperature instead of 0° C., andthe reaction time was set to 2.5 hours instead of 5 hours. The opticalpurity of the compound (21) obtained in this example is shown in Table11.

Example 15 Confirmation of α-benzylation of glycine (A5)

The compound (21) was obtained (yield 82%) in the same manner as inExample 11, except that the chiral ammonium salt ((S)-5) (1 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, and thereaction time was set to 10 hours instead of 5 hours. It was confirmedby TLC that part of the starting material remained. The optical purityof the compound (21) obtained in this example is shown in Table 11.

Example 16 Confirmation of α-benzylation of glycine (A6)

The compound (21) was obtained (yield 96%) in the same manner as inExample 11, except that the chiral ammonium salt ((S)-5) (1 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, thereaction temperature was set to room temperature instead of 0° C., andthe reaction time was set to 2.5 hours instead of 5 hours. The opticalpurity of the compound (21) obtained in this example is shown in Table11.

TABLE 11 Optical Phase- purity (% ee), transfer Reaction (Absolutecatalyst condition Yield (%) configuration) Example 11 (S)-4a 0° C., 5hours 97 96, (R) Example 12 (S)-4a Room quantita- 91, (R) temperature,tive 3 hours Example 13 (S)-4b 0° C., 4 hours 95 86, (R) Example 14(S)-4b Room 92 68, (R) temperature, 2.5 hours Example 15 (S)-5 0° C., 10hours 82 90, (R) Example 16 (S)-5 Room 96 98, (R) temperature, 2.5 hours

As shown in Table 11, it is found that all compounds (chiral ammoniumsalts) contained in Formula (I) of the present invention contribute tothe α-benzylation of glycine as a phase-transfer catalyst. It is foundthat, in particular, when the reaction conditions are adjusted, theyield and the optical purity of the product are significantly improved,which is useful in the production of optically active α-amino acidderivatives and optically active α-amino acids using these compounds.

Example 17 Confirmation of α-benzylation of glycine (B1)

A mixture of the chiral ammonium salt ((S)-4a) obtained in Example 5 (1mol %; phase-transfer catalyst) and ethyl iodide (8 equivalents) as thecompound represented by R¹⁸—W in the above formula was added to amixture of 50% KOH aqueous solution (1 mL) and a toluene solution (1.5mL) of N-(biphenylmethylene)glycine tert-butyl ester (20) (88.6 mg, 0.3mmol), and the resultant was stirred vigorously under an argonatmosphere at 0° C. for 8 hours. Completion of the reaction wasconfirmed by TLC, and then the mixture was poured into water andextracted with ether. The organic extract was washed with brine anddried over Na₂SO₄. The solvent was evaporated under reduced pressure,and then a residual oil was purified by silica gel column chromatography(ether/hexane= 1/10 as the eluent) to give the corresponding compound(21) ((R)-tert-buty N-(diphenylmethylene) phenylalanine) (yield 92%).The optical purity of the compound (21) obtained in this example wasanalyzed by HPLC (Daicel Chiralcel OD, eluent: hexane/2-propanol=100/1)._(The optical purity of the compound ()21) obtained in this example isshown in Table 12.

Example 18 Confirmation of α-benzylation of glycine (B2)

The compound (21) was obtained (yield 90%) in the same manner as inExample 17, except that allyl bromide (3 equivalents) was used insteadof ethyl iodide as the compound represented by R¹⁸—W in the aboveformula, and the reaction time was set to 2.5 hours instead of 8 hours.The optical purity of the compound (21) obtained in this example isshown in Table 12.

Example 19 Confirmation of α-benzylation of glycine (B3)

The compound (21) was obtained (yield 82%) in the same manner as inExample 17, except that propargyl bromide (3 equivalents) was usedinstead of ethyl iodide as the compound represented by R¹⁸—W in theabove formula, and the reaction time was set to 10 hours instead of 8hours. The optical purity of the compound (21) obtained in this exampleis shown in Table 12.

Example 20 Confirmation of α-benzylation of glycine (B4)

The compound (21) was obtained (yield 94%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (1 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, benzylbromide (1.5 equivalents) was used instead of ethyl iodide as thecompound represented by R¹⁸—W in the above formula, and the reactiontime was set to 4 hours instead of 8 hours. The optical purity of thecompound (21) obtained in this example is shown in Table 12.

Example 21 Confirmation of α-benzylation of glycine (B5)

The compound (21) was obtained (yield 94%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (1 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, propargylbromide (1.5 equivalents) was used instead of ethyl iodide as thecompound represented by R¹⁸—W in the above formula, and the reactiontime was set to 3 hours instead of 8 hours. The optical purity of thecompound (21) obtained in this example is shown in Table 12.

Example 22 Confirmation of α-benzylation of glycine (B6)

The compound (21) was obtained (yield 92%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (1 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, allylbromide (1.5 equivalents) was used instead of ethyl iodide as thecompound represented by R¹⁸—W in the above formula, and the reactiontime was set to 3.5 hours instead of 8 hours. The optical purity of thecompound (21) obtained in this example is shown in Table 12.

Example 23 Confirmation of α-benzylation of glycine (B7)

The compound (21) was obtained (yield 86%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (1 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, and thereaction time was set to 10 hours instead of 8 hours. The optical purityof the compound (21) obtained in this example is shown in Table 12.

Example 24 Confirmation of α-benzylation of glycine (B8)

The compound (21) was obtained (yield 92%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (0.2 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, propargylbromide (2 equivalents) was used instead of ethyl iodide as the compoundrepresented by R¹⁸—W in the above formula, the reaction temperature wasset to 20° C. instead of 0° C., and the reaction time was set to 6 hoursinstead of 8 hours. The optical purity of the compound (21) obtained inthis example is shown in Table 12.

Example 25 Confirmation of α-benzylation of glycine (B9)

The compound (21) was obtained (yield 95%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (0.5 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, allylbromide (1.5 equivalents) was used instead of ethyl iodide as thecompound represented by R¹⁸—W in the above formula, the reactiontemperature was set to 20° C. instead of 0° C., and the reaction timewas set to 5 hours instead of 8 hours. The optical purity of thecompound (21) obtained in this example is shown in Table 12.

Example 26 Confirmation of α-benzylaton of glycine (B10)

The compound (21) was obtained (yield 81%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (1 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, thereaction temperature was set to 20° C. instead of 0° C., and thereaction time was set to 10 hours instead of 8 hours. The optical purityof the compound (21) obtained in this example is shown in Table 12.

Example 27 Confirmation of α-benzylation of glycine (B11)

The compound (21) was obtained (yield 93%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (0.5 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, benzylbromide (1.2 equivalents) was used instead of ethyl iodide as thecompound represented by R¹⁸—W in the above formula, the reactiontemperature was set to 20° C. instead of 0° C., and the reaction timewas set to 5 hours instead of 8 hours. The optical purity of thecompound (21) obtained in this example is shown in Table 12.

Example 28 Confirmation of α-benzylation of glycine (B12)

The compound (21) was obtained (yield 94%) in the same manner as inExample 17, except that the chiral ammonium salt ((S)-5) (0.1 mol %)obtained in Example 10 was used instead of the chiral ammonium salt((S)-4a) obtained in Example 5 as the phase-transfer catalyst, benzylbromide (1.5 equivalents) was used instead of ethyl iodide as thecompound represented by R¹⁸—W in the above formula, the reactiontemperature was set to 20° C. instead of 0° C., and the reaction timewas set to 12 hours instead of 8 hours. The optical purity of thecompound (21) obtained in this example is shown in Table 12.

TABLE 12 Phase-transfer Optical purity (% ee), catalyst Reaction(Absolute (mol %) R¹⁸-W (equivalent) condition Yield (%) configuration)Example 17 (S)-4a (1) Ethyl iodide (8) 0° C., 8 hours 92 81, (R) Example18 (S)-4a (1) Allyl bromide (3)  0° C., 2.5 hours 90 93, (R) Example 19(S)-4a (1) Propargyl bromide (3)  0° C., 10 hours 82 90, (R) Example 20(S)-5 (1) Benzyl bromide (1.5) 0° C., 4 hours 94 86, (R) Example 21(S)-5 (1) Propargyl bromide (1.5) 0° C., 3 hours 94 87, (R) Example 22(S)-5 (1) Allyl bromide (1.5)  0° C., 3.5 hours 92 88, (R) Example 23(S)-5 (1) Ethyl iodide (3)  0° C., 10 hours 86 90, (R) Example 24 (S)-5(0.2) Propargyl bromide (2) 20° C., 6 hours  92 91, (R) Example 25 (S)-5(0.5) Allyl bromide (1.5) 20° C., 5 hours  95 93, (R) Example 26 (S)-5(1) Ethyl iodide (3) 20° C., 10 hours 81 90, (R) Example 27 (S)-5 (0.5)Benzyl bromide (1.2) 20° C., 5 hours  93 95, (R) Example 28 (S)-5 (0.1)Benzyl bromide (1.5) 20° C., 12 hours 94 95, (R)

As shown in Table 12, it is found that all compounds (chiral ammoniumsalts) contained in Formula (I) of the present invention contribute tothe α-benzylation of glycine as a phase-transfer catalyst. It is foundthat, in particular, when the type of compound represented by R¹⁸—W inthe above formula, the reaction conditions, and the like are adjusted,the yield and the optical purity of the product are significantlyimproved, which is useful in the production of optically active α-aminoacid derivatives and optically active α-amino acids using thesecompounds.

INDUSTRIAL APPLICABILITY

According to the present invention, a chiral phase-transfer catalysthaving a simpler structure is provided. This phase-transfer Catalyst canbe produced by a smaller number of process steps than conventional ones,which leads to a reduction in the production cost. Such a phase-transfercatalyst is extremely useful in the synthesis of α-alkyl-α- amino acidsand derivatives thereof, and α,α-dialkyl-α-amino acids and derivativesthereof. The amino acids and their derivatives thus synthesized play animportant and special role in the design of peptides having enhancedactivity (pharmacological or physiological activity, for example), aseffective enzyme inhibitors, and as chiral building blocks for thesynthesis of compounds having various biological activities. Therefore,they are useful for the development of novel foods and pharmaceuticals.

1-25. (canceled)
 26. A compound represented by Formula (I) below:

wherein R² and R^(2′) are each independently: a hydrogen atom; or anaryl group, wherein the aryl group may be substituted with at least onegroup selected from the group consisting of: a C₁ to C₄ alkyl group thatmay be branched and that may be substituted with a halogen atom, a C₁ toC₅ alkoxy group that may be branched and that may be substituted with ahalogen atom, an aryl group that may be substituted with a halogen atomor a C₁ to C₄ alkyl group that may be branched and that may besubstituted with a halogen atom, and a halogen atom; R³ and R^(3′) areeach independently: a C₁ to C₅ alkoxy group that may be substituted witha halogen atom and/or an aryl group, and/or that may be branched or forma cyclic group; R⁴ and R^(4′) are both aryl groups, wherein the arylgroup may be substituted with at least one group selected from the groupconsisting of: a C₁ to C₄ alkyl group that may be branched and that maybe substituted with a halogen atom, a C₁ to C₅ alkoxy group that may bebranched and that may be substituted with a halogen atom, an aryl groupthat may be substituted with a halogen atom or a C₁ to C₄ alkyl groupthat may be branched and that may be substituted with a halogen atom,and a halogen atom; R⁷ and R⁸ are each independently a group selectedfrom the group consisting of: (i) a C₁ to C₃₀ alkyl group that may bebranched or form a cyclic group and that may be substituted with ahalogen atom; (ii) a C₂ to C₁₂ alkenyl group that may be branched orform a cyclic group and that may be substituted with a halogen atom;(iii) a C₂ to C₁₂ alkynyl group that may be branched or form a cyclicgroup and that may be substituted with a halogen atom; and (iv) an arylgroup, wherein the aryl group may be substituted with at least one groupselected from the group consisting of: a C₁ to C₄ alkyl group that maybe branched and that may be substituted with a halogen atom, a C₁ to C₅alkoxy group that may be branched and that may be substituted with ahalogen atom, an aryl group that may be substituted with a halogen atomor a C₁ to C₄ alkyl group that may be branched and that may besubstituted with a halogen atom, and a halogen atom; or R⁷ and R⁸ aretaken together to form a divalent group selected from the groupconsisting of: —(CH₂)_(n)— (where m is an integer from 2 to 8);

(where R²⁷, R²⁸, R²⁹,R³², R³³ and R³⁴ are each independently a groupselected from the group consisting of: a hydrogen atom; a C₁ to C₈ alkylgroup that may be branched or form a cyclic group, and/or that may besubstituted with a halogen atom; a C₂ to C₈ alkenyl group that may bebranched or form a cyclic group, and/or that may be substituted with ahalogen atom; a C₂ to C₈ alkynyl group that may be branched or form acyclic group, and/or that may be substituted with a halogen atom; anaryl group, which may be substituted with a C₁ to C₄ alkyl group thatmay be substituted with a halogen atom, a C₁ to C₃ alkoxy group that maybe substituted with a halogen atom, an aryl group that may besubstituted with a C₁ to C₄ alkyl group that may be substituted with ahalogen atom, a cyano group, a halogen atom, a nitro group, —NR³⁰R³¹(where R³⁰ and R³¹ are each independently a hydrogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom), or a cyclic amino group that is formed by a C₂ to C₈alkylene group; and an aralkyl group, which has an aryl moiety that maybe substituted with a C₁ to C₄ alkyl group that may be substituted witha halogen atom, a C₁ to C₃ alkoxy group that may be substituted with ahalogen atom, a cyano group, a halogen atom, a nitro group, —NR³⁰ R³¹(where R³⁰ and R³¹ are each independently a hydrogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom), or a cyclic amino group that is formed by a C₂ to C₈alkylene group), and X⁻ is an anion selected from the group consistingof a halide anion, SCN⁻, HSO₄ ⁻, HF₂ ⁻, CF₃SO₃ ⁻, CH₃—C₆H₄—SO₃ ⁻, andCH₃SO₃ ⁻.
 27. The compound of claim 26, wherein R² and R^(2′) of thecompound represented by Formula (I) are both hydrogen atoms.
 28. Thecompound of claim 26, wherein R² and R^(2′) of the compound representedby Formula (I) are both aryl groups, wherein the aryl group may besubstituted with at least one group selected from the group consistingof: a C₁ to C₄ alkyl group that may be branched and that may besubstituted with a halogen atom, a C₁ to C₅ alkoxy group that may bebranched and that may be substituted with a halogen atom, an aryl groupthat may be substituted with a halogen atom or a C₁ to C₄ alkyl groupthat may be branched and that may be substituted with a halogen atom,and a halogen atom.
 29. A method for producing the compound representedby Formula (I) of claim 26, comprising: reacting a compound representedby Formula (II) below:

with a secondary amine represented by Formula (III) below:

in an organic solvent in the presence of an acid-scavenging agent,wherein in Formula (II), R² and R^(2′) are each independently: ahydrogen atom; or an aryl group, wherein the aryl group may besubstituted with at least one group selected from the group consistingof: a C₁ to C₄ alkyl group that may be branched and that may besubstituted with a halogen atom, a C₁ to C₅ alkoxy group that may bebranched and that may be substituted with a halogen atom, an aryl groupthat may be substituted with a halogen atom or a C₁ to C₄ alkyl groupthat may be branched and that may be substituted with a halogen atom,and a halogen atom; R³ and R^(3′) are each independently: a C₁ to C₅alkoxy group that may be substituted with a halogen atom and/or an arylgroup, and/or that may be branched or form a cyclic group; R⁴ and R^(4′)are both aryl groups, wherein the aryl group may be substituted with atleast one group selected from the group consisting of: a C₁ to C₄ alkylgroup that may be branched and that may be substituted with a halogenatom, a C₁ to C₅ alkoxy group that may be branched and that may besubstituted with a halogen atom, an aryl group that may be substitutedwith a halogen atom or a C₁ to C₄ alkyl group that may be branched andthat may be substituted with a halogen atom, and a halogen atom, R⁷ andR⁸ are each independently a group selected from the group consisting of:(i) a C₁ to C₃₀ alkyl group that may be branched or form a cyclic groupand that may be substituted with a halogen atom; (ii) a C₂ to C₁₂alkenyl group that may be branched or form a cyclic group and that maybe substituted with a halogen atom; (iii) a C₂ to C₁₂ alkynyl group thatmay be branched or form a cyclic group and that may be substituted witha halogen atom; and (iv) an aryl group, wherein the aryl group may besubstituted with at least one group selected from the group consistingof: a C₁ to C₄ alkyl group that may be branched and that may besubstituted with a halogen atom, a C₁ to C₅ alkoxy group that may bebranched and that may be substituted with a halogen atom, an aryl groupthat may be substituted with a halogen atom or a C₁ to C₄ alkyl groupthat may be branched and that may be substituted with a halogen atom,and a halogen atom; or R⁷ and R⁸ are taken together to form a divalentgroup selected from the group consisting of: —(CH₂)_(m)— (where m is aninteger from 2 to 8);

(where R²⁷, R²⁸, R²⁹, R³², R³³ and R³⁴ are each independently a groupselected from the group consisting of: a hydrogen atom; a C₁ to C₈ alkylgroup that may be branched or form a cyclic group, and/or that may besubstituted with a halogen atom; a C₂ to C₈ alkenyl group that may bebranched or form a cyclic group, and/or that may be substituted with ahalogen atom; a C₂ to C₈ alkynyl group that may be branched or form acyclic group, and/or that may be substituted with a halogen atom; anaryl group, which may be substituted with a C₁ to C₄ alkyl group thatmay be substituted with a halogen atom, a C₁ to C₃ alkoxy group that maybe substituted with a halogen atom, an aryl group that may besubstituted with a C₁ to C₄ alkyl group that may be substituted with ahalogen atom, a cyano group, a halogen atom, a nitro group, —NR³⁰ R³¹(where R³⁰ and R³¹ are each independently a hydrogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom), or a cyclic amino group that is formed by a C₂ to C₈alkylene group; and an aralkyl group, which has an aryl moiety that maybe substituted with a C₁ to C₄ alkyl group that may be substituted witha halogen atom, a C₁ to C₃ alkoxy group that may be substituted with ahalogen atom, a cyano group, a halogen atom, a nitro group, —NR³⁰ R³¹(where R³⁰ and R³¹ are each independently a hydrogen atom or a C₁ to C₄alkyl group that may be branched and that may be substituted with ahalogen atom), or a cyclic amino group that is formed by a C₂ to C₈alkylene group).
 30. The method of claim 29, wherein R² and R^(2′) ofthe compound represented by Formula (II) are both hydrogen atoms. 31.The method of claim 29, wherein R² and R^(2′) of the compoundrepresented by Formula (II) are both aryl groups, wherein the aryl groupmay be substituted with at least one group selected from the groupconsisting of: a C₁ to C₄ alkyl group that may be branched and that maybe substituted with a halogen atom, a C₁ to C₅ alkoxy group that may bebranched and that may be substituted with a halogen atom, an aryl groupthat may be substituted with a halogen atom or a C₁ to C₄ alkyl groupthat may be branched and that may be substituted with a halogen atom,and a halogen atom.